A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium
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International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013 Available online at http://www.ijsrpub.com/ijsres
ISSN: 2322-4983; ©2013 IJSRPUB
http://dx.doi.org/10.12983/ijsres-2013-p202-216
202
Review Paper
A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis:
Nickel and Cadmium
Zienab Saedi, Shahin Gavanji*, Sahar Davodi
1Department of Biotechnology, Faculty of Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran
*Corresponding Author: shahin.gavanji@yahoo.com
Received 11 June 2013; Accepted 25 July 2013
Abstract. Heavy metals constitute an important class of environmental contaminants that classified as human carcinogens
according to the US Environmental Protection Agency and the International Agency for Research on Cancer. They affect
human health through occupational and environmental exposure. Multiple experimental epidemiological studies indicate that
heavy metals such as Nickel and Cadmium can induce several types of cancer significantly pulmonary cancers, but the
mechanisms underlying the carcinogenesis are not well understood yet. This metals are genotoxic elements for human, while
they are typically weak mutagens, indicating that indirect mechanisms may be primary responsible for their genotoxicity.
Several studies suggest that epigenetic mechanisms may play an important role in metal-induced carcinogenesis. Here, we
review studies that investigate the common mechanisms of nickel and cadmium-induced carcinogenesis, include DNA
methylation, histone modification, induction of oxidative stress, interference with DNA repair system, and interruption of cell
growth and proliferation through signaling pathway and dysregulation of tumor suppressor genes.
Key words: Nickel, Cadmium, Genotoxicity, Molecular mechanism
1. INTRODUCTION
Pollution of the biosphere with heavy metals due to
man-made activities poses an important
environmental and human health problem (Kabir et
al., 2012; Han et al., 2002; Gavanji et al., 2012).
Increasing data show a link between heavy
metal exposure and aberrant changes in both genetic
and epigenetic factors in humans. Nickel and
cadmium are heavy metals which exposure to their
compounds can induce several kinds of cancers
specially pulmonary cancer (Grimsrud et al., 2003;
Waalkes, 2000; Gavanji et al., 2013). Exposure of
Syrian hamster embryo (SHE) cells to nickel
subsulfide resulted in morphological transformation
and the transformed cells were able to induce
sarcomas in nude mice. Also the exposure of mouse
embryo fibroblast C3H/10T 1/2 cells to nickel sulfide
also led to cell transformation (Salnikow and Costa,
2000). It has been shown that cadmium can induce
malignant transformation of the human prostate
epithelial cell line (RWPE-1) (Achanzar et al., 2001).
Molecular mechanisms underlying Ni and Ca cell-
transforming ability are not well understood. Both of
them are weak mutagens and do not exhibit positive
effects in a wide range of mutation tests (IARC,
2012). Thus Several types of indirect mechanisms
have been identified that may contribute to their
genotoxic potentials, such as induction of oxidative
DNA damage and gene silencing by changes in DNA
methylation patterns (Aritaa and Costa, 2009).
2. METHODOLOGY
Firstly, based on our research about heavy Metal,
articles regarding to effects of heavy Metal on
eukaryotic cells were searched in several data bases
available through UI (University of Isfahan) library
website and Google scholar too. Referral articles (150
articles) include which were published between 1981
to 2013. Then they were reviewed during 8 months
and important points related to the effect of heavy
Metal on eukaryotic cells were studied particularly.
We, in this review, studied the molecular mechanism
of heavy Metal on eukaryotic cells.
2.1. Nickel
Nickel is a hard, silvery-white transition metal with
the atomic number 28. It is the 24th most abundant
element. The most important oxidation state of nickel
is +2. Other valences include -1, 0, +1, +3 and +4
(Tundermann et al., 2005). Nickel and its compounds
are widely used in modern industry. It is used in
conjunction with other metals to form alloys to
produce coins, jewelry, and stainless steel as well as
for nickel plating and manufacturing Ni-Cd batteries
and for catalyze the production of carbon
nanoparticles (Grandjean, 1984). The production,
Saedi et al.
A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium
203
processing, and recycling of nickel products has
resulted in a high level of pollution such that nickel
contamination now occurs in water, soil and the
ambient air (Lippmann et al., 2006). Combustion of
fossil fuels produces the greatest contribution of
nickel compounds in the ambient air (Merian, 1984).
Nickel compounds can enter the body through
inhalation, ingestion, and dermal absorption
(Grandjean, 1984) and they have been found to be
carcinogenic based upon numerous epidemiological
studies (Doll et al., 1970). The International Agency
for Research on Cancer (IARC) evaluated the
carcinogenicity of nickel in 1990. All Ni (II)
compounds were recognized as human carcinogens
(Group 1) and metallic nickel is classified as possibly
carcinogenic to humans (Group 2B) (kasprzak et al.,
2003). It has been found that exposures to nickel
compounds are associated with increased nasal and
lung cancer incidence (Andersen., 1996; Grimsrud et
al., 2003). A summary of toxicity of various nickel
species and compounds are shown in table 1. The
carcinogenicity of nickel has been explained by
several mechanisms such as inhibition of DNA repair
(Woźniak and Błasiak, 2004), oxidative stress (Chen
et al., 2003) and deregulation normal growth control
(Salnikow and Zhitkovich, 2008) which are discussed
below.
2.2. Cellular uptake
Carcinogenesis of metal compounds depends on their
ability to enter the cell and it’s probably related to
their solubility in water. Water-soluble nickel
compounds possess lower toxic and carcinogenic
potential as compared to insoluble nickel compounds
because Water-soluble compounds such as Nickel
acetate, bromide, chloride, iodide, nitrate and sulfate
are quickly flushed from tissue and therefore has a
limited ability to enter the cell via the divalent metal
transporter 1 (DMT1) (Funakoshi et al., 1997;
Denkhaus and Salnikow, 2002). Some of soluble
nickel compounds enters cell via calcium channels
(Refsvik and Andreassen, 1995; Funakoshi et al.,
1997). NiCI2 and NiSO4 enter cells with relative ease,
possibly following conjugation with serum proteins or
amino acids such as histidine (Costa et al., 1981).
Insoluble nickel compounds possibly enter the cell
through phagocytosis. many results clearly indicate
that water-insoluble nickel compounds such as
crystalline nickel sulfide(Nis) and crystalline nickel
sub sulfide (Ni3S2) phagocytized by a large variety of
different cells in culture (Costa et al., 1981). Ni
carbonyl, a highly toxic form of Ni, is lipid soluble
allowing it to pass through the cellular membrane and
in turn significant absorption occurs through
inhalation and skin contact )Muñoz and Costa, 2012).
Numerous studies point to the cell nucleus as the site
of nickel attack (Salnikow et al., 1994; Lee et al.,
1995). Nickel chloride has been shown in different
cell lines in culture to be transported to the nucleus
(Edwards et al., 1998; Schwerdtle and Hartwig, 2006).
2.3. Induction of oxidative stress
Nickel compounds are able to cause the cell
transformation and chromatin damage )Cai and
Zhuang, 1999; M’Bemba-Meka et al., 2005) but they
are not mutagenic in a wide range of bacterial
mutagenesis assays and are only weakly mutagenic in
cultured mammalian cells (Biggart and Costa, 1986;
klein et al., 1991; Kerckaert et al., 1996). One possible
explanation for this is nickel cause the DNA damage
and cell transformation via generation of reactive
oxygen species (ROS) (Salnikow and Costa, 2000).
Like many other carcinogenic metals, nickel
compounds are able to induce the formation of ROS.
Nickel is a redox-active metal that can catalyse
Fenton-type reactions (Huang et al., 1993; Chen et al.,
2003). In cells treated with nickel compounds,
increase in DNA stand breaks, DNA–protein
crosslinks and sister chromatid exchange was
observed and these are shown to result from the
increase in reactive oxygen species (Chakrabarti et al.,
2001; M’Bemba-Meka et al., 2005, 2007). Nickel (II)
ions can catalyze the generation of OH radicals from
H2O2. These radicals attack the DNA bases and cause
to formation of typical OH-induced products of DNA
bases in isolated human chromatin (Nackerdien et al.,
1991; Lloyd and Phillips, 1999).
2.4. Inhibition of DNA repair
There is accumulating evidence that carcinogenic
nickel compounds disturb DNA repair systems by
diverse mechanisms. Ni (II) disturbed the first step of
nucleotide excision repair (NER), that involves
recognition of damaged DNA (Hartmann and
Hartwig, 1998). It had found that repair inhibition by
Ni (II) may be caused by the displacement of zinc in
zinc finger structures of DNA repair proteins such as
XPA protein (Asmuss et al., 2000a). There is some
evidence that Ni (II) inhibits the repair of O6-
methylguanine via silencing of the DNA repair gene
O6-methylguanine DNA methyltransferase (MGMT)
expression (Iwitzki et al., 1998; Ji et al., 2008).
Soluble nickel chloride also inhibits base excision
repair (BER), via inhibition the base-excision repair
enzyme, 3-methyladenine-DNA glycosylase II (Dally
and Hartwig, 1997; Wang et al., 2006). Nickel
Inhibition of DNA Repair may be mediated by
Reactive Oxygen Species. Ni enhances the
intracellular H2O2 level, which may increase
International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013
204
oxidative damage in DNA repair enzymes and thereby
reduce this enzymes activity (Lynn et al., 1997;
Gavanji et al., 2013). Nickel Ions Inhibit DNA Repair
Enzyme ABH2 and Histone Demethylase JMJD1A.
These enzymes are iron- and 2-oxoglutarate-
dependent dioxygenases that uses the 2-His-1-
carboxylate motif to bind the cofactor ferrous iron ion
at their active sites. Ni (II) competes with Fe(II) and
replaces it at the iron-binding site thus inhibit enzyme
activity (Chen et al., 2010).
2.5. Epigenetic mechanisms, gene silencing and
Deregulation of cell proliferation
The epigenetic dysregulation of gene expression is
one of primary causes in cancer (Egger et al., 2004;
Ke et al., 2006). Silencing of tumor suppressor genes
by epigenetic mechanisms represents one of the main
mechanisms of nickel carcinogenesis. Both water-
soluble and water-insoluble nickel compounds are
able to cause gene silencing via diverse epigenetic
mechanisms (Costa et al., 2005). Nickel inactivates
transcription of genes by inducing DNA methylation
and chromatin compaction (Lee et al., 1995). So it
seems that Heterochromatinization is a potential
mechanism of nickel-induced carcinogenesis (Ellen et
al., 2009). Nickel compounds cause posttranslational
epigenetic modifications of histone proteins, thus
derailing the normal programming of gene expression
(Sutherland and Costa, 2003; Zhou et al., 2009). It has
been shown that the transcriptional suppression of
MGMT (O6-methylguanine DNA methyltransferase)
expression in NiS-transformed cells mediate by
epigenetic Histone modifications at the promoter
region of MGMT gene (Ji et al., 2008). Recently,
Arita et al, demonstrated that exposure to nickel
compounds, can induce changes in global levels of
posttranslational histone modifications in peripheral
blood mononuclear cells (Arita et al., 2012). Recent
studies show that cells treated with nickel have
decreased histone acetylation, and altered histone
methylation patterns (Broday et al., 2000; Sutherland
and Costa, 2003; Chen et al., 2006). Nickel exposure
increased the level of H3K4 trimethylation in both the
promoters and coding regions of several genes
including CA9 and NDRG1 that were increased in
expression in A549 cells (Tchou-Wong et al., 2011).
It also increased lysine 9 in histone H3 (H3K9)
dimethylation by inhibiting the demethylating enzyme
JHDM2A (Chen et al., 2010). Nickel is a potent
inhibitor of histone H4 acetylation in yeast and in
mammalian cells (Broday et al., 2000). The loss of
histone acetylation and DNA methylation worked
together in gptgene silencing in G12 transgenic cell
line by nickel (Zoroddu et al., 2002; Yan et al., 2003).
Nickel also causes ubiquination and phosphorylation
of histones (Karaczyn et al., 2006; Ke et al., 2008).
Nickel ions may deregulate cell proliferation by
inactivating apoptotic processes. P53 is an important
tumor suppressor gene and transcription factor which
involved in the regulation of cell proliferation and
apoptosis (Bates and Vousden, 1999). Nickel ions
inhibit binding of p53 to scDNA and to
its consensus sequence in linear DNA fragments
(Palecek et al., 1999). In another study it was
observed that nickel-immortalized cells revealed
abnormal p53 expression and a T--C transition
mutation in codon 238 (Maehle et al., 1992). The
Fragile Histidine Triad (FHIT) gene is a tumor
suppressor gene that locates in a fragile chromosomal
site sensitive to deletions. in tumors the expression of
FHIT gene was frequently found to be reduced even
lost (Kasprzaker et al., 2003). It was found in vitro
that Ni (ІІ) had strong inhibitory effect on the
enzymatic activity of Fhit protein. Also in nickel-
induced tumors, aberrant transcripts or loss of
expression of the FHIT gene and Fhit protein was
observed (Kowara et al., 2002; Ji et al., 2006). It
appears that amplification of certain oncogenes is a
common correlate of the progression of some nickel
induced tumors and cancers (Sunderman et al., 1990).
Elevated expression of oncogenic c-myc mRNA was
reported in nickel transformed mouse 10T1/2 cells
(Landolph, 1994). In the past few years, many studies
have been conducted on the molecular mechanisms of
nickel carcinogenesis which focused on the activation
of proto-oncogenes and inactivation of anti-oncogenes
caused by gene amplification, DNA methylation,
chromosome condensation, and so on that were
induced by nickel. However, the researches on
tumorigenic molecular mechanisms regulated by
microRNAs (miRNAs) are rare. By establishing a
cDNA library of miRNA from rat muscle tumor tissue
induced by Ni3S2, Zhang et al (2013) found that the
expression of miR-222 was significantly up regulated
in tumor tissue compared with the normal tissue. They
concluded that miR-222 may promote cell
proliferation infinitely during nickel-induced tumor
genesis in part by regulating the expression of its
target genes CDKN1B and CDKN1C.
2.6. Cadmium
Cadmium (atomic number, 48; relative atomic mass,
112.41) is a heavy metal that belongs to group IIB of
the periodic table. The oxidation state of about all
cadmium compounds is +2, although a few
compounds have been reported in that it is +1. (IARC,
1993).Cadmium (cd) is a toxic transition metal that
has been designated a human carcinogen by the
National Toxicology program. Cadmium found
naturally in ores together with zinc, lead and copper.
Saedi et al.
A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium
205
Sources of human exposure to cadmium include
certain batteries manufacturing, some electroplating
processes and consumption of tobacco products.
Multiple epidemiological studies have linked
occupational exposure to cadmium with pulmonary
cancer, while fewer studies have linked it to prostate,
renal, liver, hematopoietic system, urinary bladder,
pancreatic, and stomach cancers (Waalkes and Misra,
1996; Waalkes, 2000; Hu et al., 2002). A summary of
toxicity of various cadmium species and compounds
are shown in table 2. Cadmium is a weak mutagenic
and has a poorly DNA binding affinity, suggesting
that it promote carcinogenesis through epigenetic
mechanisms (Arita and Costa, 2009). suggested
mechanisms for Cd-carcinogenesis include such as
formation of reactive oxygen species (ROS) and/or
interference with anti-oxidative enzymes, inhibition of
DNA repair enzymes, deregulation of cell
proliferation, suppressed apoptosis (Waalkes, 2003).
2.7. Cellular uptake
Investigation of the cellular cadmium uptake
mechanism in the rat jejunum showed that, this
process is done through nonspecific binding to anionic
sites on the membrane, then followed by a
temperature –dependent and limiting internalization
step (Foulkes., 1989). Hinkle indicated that a major
mechanism for cellular uptake of cadmium is
dependent to voltage-sensitive calcium channels
(Patricia et al., 1987). Studies showed that Mn
transport system is used for cellular dc uptake.
Divalent metal transporter 1 (DMT1) is the only
known mammalian transporter involved in the uptake
of both Cd and Mn (Himeno et al., 2002). Exgenous
glutathione (GSH) prevent cellular uptake through
form a complex with cadmium outside of the cells
(Kang, 1992).
2.8. Induction of oxidative stress
Cadmium is a bivalent cation and unable to produce
reactive oxygen speacies (ROS) directly, nevertheless
cd-induced oxidative estress reported in multitude
studies (Wang et al. 2004, Valko et al. 2005; Zhou et
al., 2009). Cadmium sulfide enhanced hydrogen
peroxide production in human leukocytes, and
cadmium chloride induced the formation of
superoxide in rat and human phagocytes (Sugiyama,
1994). Experiments in both in vivo and in vitro,
indicated that cadmium has inhibitory effect on
antioxidant enzymes through the interaction with their
thiol groups (Stohs et al., 2001; Valko et al., 2006;
Gavanji et al., 2013). Cadmium also can replace of
copper and iron in various proteins, and hence
increase the cellular amount of free redox-active
metals (Price and Joshi, 1983; Dorta et al., 2003).cd-
exposured for long-term enhanced lipid peroxidation
and inhibited activity of superoxide dismutase (SOD)
in rat liver , kidney and testesis (Patra et al., 1999).
Investigation of cd-effects on basic motility
characteristics in bovine seminal plasma and
spermatozoa, shown that cd can increase the
development of oxidant stress so decrease of male
fertility (Tvrdá, 2013).
2.9. Inhibition of DNA repair
Cadmium also exert comutagenic effects by
disturbances several types of DNA-repair
mechanisms, i.e. base excision, nucleotide excision,
mismatch repair, and the exclusion of the pre-
mutagenic DNA precursor 7,8-dihydro- 8-oxoguanine
(Hartwig and Schwerdtle, 2002). In base-excision
repair, sub-lethal concentrations of cadmium do not
generate oxidative damage as such, but suppress the
repair of oxidative DNA damage in mammalian cells
(Dally and Hartwig, 1997; Fatur et al.,
2003).Exposure of human cells to cd low
concentration decrease removal of x-ray-induced 8-
oxoguanin ( 8-oxoG) adducts, that in turn increase the
mutation frequency, this occurs through decrease in
hOGG1 ( human8-oxoguanine-DNA glycosylase-1)
activity (Youn et al., 2005; Bravard et al., 2009).
Recently studies shown that hOGG1 significantly
reduced in the presence of in human spermatozoa
(Smith et al., 2013). On analysis dedicated microarray
in vitro shown inhibitory effects of cadmium in both
base and nucleotide exision/repair pathways
(Candéias, 2010). In nucleotide-excision repair,
cadmium suppress the removal of thymine dimers
after UV irradiation by inhibiting the incision at the
DNA lesion (Hartwig and Schwerdtle, 2002; Fatur et
al., 2003). Schwerdtle et al. indicated that cadmium
compounds such as CdO and soluble CdCl2 inhibit the
nucleotide excision repair in a dose-dependent manner
at low concentration (2010). Cadmium suppress the 8-
oxo-dGTPases activity, therefore disturbs the
exclusion of 8-oxo-dGTP, a product of oxidative
modification of dGTP, from the nucleotide pool
(Bialkowski and Kasprzak, 1998). Additionally cd
can displace the zinc in DNA-repair proteins such as
xerodermapigmentosum group A (XPA) that is
involved in nucleotide-excision repair and inhibit their
function (Asmuss et al., 2000b). Recent evidence
suggests that existence of Microsatellite instability,
one of the phenotypes of defective DNA mismatch
repair, in nuclear indicating genotoxic effects induced
by cadmium (Oliveira et al., 2012).
International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013
206
Table 1: toxicity and carcinogenicity of various nickel species and compounds
2.8. Epigenetic mechanisms, gene silencing and
Deregulation of cell proliferation
Most studies indicate cadmium is poorly mutagenic,
and has a weak DNA binding affinity, so probably
promote carcinogenesis through indirect or epigenetic
mechanism including aberrant activation of oncogenes
and suppression of apoptosis (Waalkes, 2003; Arita
and Costa, 2009). Multiple studies are shown that
cadmium can induce epigenetic effects in experiment
Name Formula Solubility Reference Methods Results
Nickel metal
powder
Ni Insoluble Oller et al, 2008 Wistar rat inhalation study increased incidence of neoplasm of
the respiratory tract was not observed
Nickel subsulfide
Ni3S2 Low National Toxicology
Program, 1996
In f344/n rats and b6c3fl
mice inhalation study
there was clear evidence of
carcinogenic activity of nickel
subsulfide in male F344/N rats based
on increased incidences of
alveolar/bronchiolar adenoma,
carcinoma
Nickel sulfide
NiS
Crystalline
(low)
Amorphous
(low)
Costa, 1991
Literature Review
Amorphous nickel sulfide is a weak
carcinogen compared to crystalline
nickel sulfide, likely due to
differences in extent of endocytosis
Nickel arsenide
(orcelite)
Ni5As2
Low Sunderman and
Kilmer, 1983
Intramuscular Injection to
male Fischer rats
Within 2 years, the incidences of
sarcomas at the injection site were
17/20 (85%) in Ni5As2-treated rats
Nickel carbonate NiCO3 Low Ciccarelli and
Wetterhahn, 1982
Intraperitoneal Injection to
rats
A dose response to both single-strand
breaks and cross-links was observed
in kidney nuclei
Nickel(II) oxide NiO Low Clemens and
Landolph, 2003
Nickel refinery dust
phagocytized by
cultured mouse embryo
cells
Equally cytotoxic to orcelite-
containing particles but no dose-
dependent morphological
transformation observed
Nickel(III)
oxide
Ni2O3
Variable
depending on
calcination
temperature
Schwerdtle et al,
2002
Human lung cell culture
As a co-carcinogen, nickel oxide
inhibited DNA repair
Nickel chromate NiCrO4 Insoluble Sunderman, 1984 single intramuscular
injection to male Fischer
rats
Within 2 years, the incidences of
sarcomas at the injection site were
(6%) in NiCrO4-treated rats
Nickel(II) sulfate
NiSO4 High Ohshima, 2003
V79 Chinese hamster cells Induced genetic and chromosomal
instability
Kasprzak et al, 1983 Intramuscular Injection to
rats
No tumors were found in animals
which had been injected i.m. with 15
doses of 4.4 mumol of NiSO4
Saedi et al.
A Review of Genetic and Epigenetic Mechanisms in Heavy Metal Carcinogenesis: Nickel and Cadmium
207
animals and mammalian cells in vitro (Martinez-
Zamudio and Ha, 2011; Wang et al., 2012; Waalkes,
2003; DFG, 2006). Sevral studies have reported that
cadmium can induce changes in global and gene
specific DNA methylation levels (Takiguchi, 2003;
Benbrahim-Tallaa, 2007; Huang, 2008). Cd can alter
the epigenetic programming in chick embryos through
down regulation of DNA methyltransferases and
following diminishment of DNA methylation (Doi et
al., 2011). In vitro and ex vivo experiments shown
that cd inhibit DNA methyltransferase (MeTase) in a
noncompetitive manner with DNA , possibly through
an interaction with the methyltransferase DNA
binding domain (Takiguchi et al., 2003). Gene-
specific DNA hypermethylation and gene silencing
have been reported in cadmium-exposed cells,
including the p16INK4a, RASSF1A and MT-1 genes (
Takiguchi et al., 2003; Benbrahim-Tallaa et al., 2007).
It has been proposed that the teratogenic effect of Cd
could also be mediated by epigenetic mechanisms,
because altered DNA methylation has been linked to
ventral body wall defect (VBWD) in chick embryos
after Cd treatment (Doi et al., 2011; Menoud and
Schowing., 1987; Thompson and Bannigan, 2001).
These data suggest that Cd may act as a teratogen to
induce VBWD by perturbing DNA methylation.
Benbrahim reported that cadmium exposure During
the 10-weeks induced malignant transformation,
increased activity DNA methylteransferase (DNMT)
that were associated with over-expression of
DNMT3b. This pattern DNA hypermethylation
together with up-regulation of DNMT3b may provide
biomarkers to specifically identify cadmium-induced
human prostate cancers (Benbrahim-Tallaa et al.,
2007). Cd – exposed human embryo lung fibroblasts
(HLF) increase both global DNA methylation and
DNMT activity. Also significantly elevated growth
rates of the HLF cells, decreased cell population of
G0/G1-phase and increased cell population of S-phase
(Jiang et al., 2008). Another study Using K562 cells
(chronic myelogenous leukemia cell line), showed
that Cd stimulated cell proliferation did not suppress
in the attenuation of ROS generation with N-
acetylcysteine (Huang et al., 2008). However,
methionine could suppress Cd-induced global DNA
hypomethylation and cell proliferation. It was
concluded by the authors that global DNA
hypomethylation, rather than ROS, is the potential
facilitator of Cd-stimulated K562 cell proliferation.
Recently studies indicate that cd-exposed DNA
methylation in early life is sex-specific and related to
lower birth (Kippler, 2013). Exposure to Cd induce
the hypermethylation of RASAL1 and KLOTHO,
associated-genes with renal fibro genesis, suggest that
this pattern may be an epigenetic marker of the
progress for chronic kidney disease (Zhang et al.,
2013). Epigenetic changes in expression of MT-3
were studied in human breast epithelial cancer cells
(Somji et al., 2011). These studied showed that the
MT-3 gene is silenced by histon modification of the
MT-3 promotor. Cadmium affects multitude cellular
processes, including signal transduction pathways,
cell proliferation, differentiation, and apoptosis. At
Submicromolar concentrations, cadmium stimulated
cell growth and DNA synthesis, and the proliferation
of rat myoblast, epithelial and chondrocyte cells
(Zglinicki et al., 1992) and of rat macrophages (Misra
et al., 2002). Cadmium decreased level of estrogen
receptor and other estrogen-regulated genes in human
breast caner cell line MCF-7, and induced the growth
of these cells 5-6 fold (Garcia-Morales et al., 1994).
Cadmium exposure also increased uterine weight and
density of the mammary gland and induced
tumorigenesis in the lining of the uterus (Johnson,
2003). Cadmium-induced apoptosis occurs by
Caspase-9 activation triggered by cytochrome-c in
human promyelocytic Leukemia HL-60 cells (Kondoh
et al., 2002) or through reactive oxygen species (ROS)
pathway and translocation of apoptosis-inducing
factor (AIF) from mitochondria into the nucleus
(Shih., 2004). Recently studies showed that cadmium
induce P53-dependent apoptosis in human prostate
epithelial cells (Aimola et al., 2012). Cadmium
elevates intracellular free calcium ion ([Ca2+]i) level,
leading to neuronal apoptosis partly by activating
mitogen-activated protein kinases (MAPK) and
mammalian target of rapamycin (mTOR) pathways
(Xu et al., 2011). Several studies have shown that
cadmium in addition to stimulating mitogenicdirectly,
indicate the negative controls of cell proliferation.
Subtoxic levels of cadmium can suppress the P53-
dependent cell cycle arrest in G(1) and G(2)/M phases
induced by gamma-irradiation through conformational
changes of wild-type P53(Méplan et al., 1999). It was
reported that Cd reduce and inactive expression of the
tumor suppressor genes, RASSF1A and P16, through
over expression of de novo DNA methytransferase
(Benbrahim et al., 2007). Recently, Cd has been
shown to enhance estrogen receptor alpha activity and
stimulate uterine and mammary gland growth in mic
and plays an important role in the promotion of breast
cancer (Siewit et al., 2010).
3. RESULTS AND DISCUSSION
During the past centuries, commercial and industrial
use of heavy metal compounds increased, and the
progress of industrialization has led to increased
emission of pollutants into ecosystems (Järup, 2003).
The potential anthropogenic heavy metal inputs in the
pedosphere increased tremendously after the 1950s. In
2000, the cumulative industrial age anthropogenic
International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013
208
global production of Cd and Ni was 1.1 and 36,
million tons (Fengxiang et al., 2002). The evidence
described above demonstrates that exposure to nickel
and cadmium compounds can disturb multitude
cellular processes, including signal transduction
pathways, cell proliferation, and apoptosis. The
mechanisms underlying this effects are not well
understood yet, but three predominant mechanisms
have been identified to explain Ni and Cd toxicity and
carcinogenicity: (1) interference with cellular redox
reactions and induction of oxidative stress, which may
cause oxidative DNA damage (Chen et al., 2003;
Stohs et al., 2001); (2) inhibition of DNA repair
systems resulting in genomic instability and
accumulation of critical mutations(Hartmann and
Hartwig., 1998; Fatur et al., 2003); (3) deregulation of
cell proliferation by induction of signaling pathways
or inactivation of growth controls such as tumor
suppressor genes (Palecek et al., 1999; Méplan et al.,
1999). Zhang et al (2013) identified a novel molecular
mechanism of nickel-induced tumorigenesis which
regulated by microRNAs (miRNAs). They stated that
miR-222 may promote cell proliferation infinitely
during nickel-induced tumorigenesis in part by
regulating the expression of its target genes CDKN1B
and CDKN1C. Some recent studies have suggested
that Cadmium and nickel play a role in breast cancer
development by acting as metalloestrogens--metals
that bind to estrogen receptors and mimic the actions
of estrogen (Martin et al., 2003). Aquino et al, have
discussed the various epidemiological, in vivo, and in
vitro studies that show a link between the heavy
metals, cadmium and nickel, and breast cancer
development, in a review article in 2012. One of the
potential mechanisms for nickel induced
carcinogenesis is mediated by reactive oxygen
speacies resulting oxidative estress. Nickel is a redox-
active metal that can catalyse Fenton-type reactions
(Chen et al., 2003). Unlike the nickel, cadmium is a
non-redox metal therefore unable to produce reactive
oxygen speacies directly (Wang et al., 2004). But it
can induce generation of ROS through inhibitory
effect on antioxidant enzymes by interaction with
their thiol groups (Valko et al., 2006). Cadmium
exhibit remarkable potential to inhibit DNA damage
repair, and it has been identified as a major
mechanism for its carcinogenicity (Giagenis et al.,
2006). In summary, the direct effect of toxic metals on
the genes and chromosomes such as DNA damage,
mutation and chromosomal aberrations is weak and
rare and usually observed at higher concentrations
(Hartwig, 1995). Therefore the main mechanism in
their carcinogenecity is epigenetic mechanism.
4. CONCLUSION
The aim of this review was to evaluate the potential
carcinogenicity and the general mechanism of nickel
and cadmium. Genomic mutation studies showed that
both nickel and cadmium compounds are very weak
mutant. The effects of these heavy metals on human
body which were investigated in epidemiological
studies and analytical experiments showed the
damages in the cells. These damages were caused by
the increase of free radicals and stimulation of
oxidative stress, Inhibition of DNA repair, and
deregulation of cell proliferation by Epigenetic
mechanisms.
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215
Table 2: toxicity and carcinogenicity of various cadmium species and compounds
Name Formula Solubility Reference Methods Results
Cadmium Cd Insoluble Person et al, 2013 exposing the peripheral
lung epithelia cell line,
HPL-1D, to a low level
of cadmium
induces cancer cell characteristics
in human lung cells
Cadmium
acetate
Cd(CH3COO)2 Soluble Yang, 1998 Exposing Chinese
hamster ovary (CHO)-
K1 cells to cadmium
acetate
decreased the colony-forming
ability of cells and induced
mutation frequency in the
hypoxanthine (guanine)
phosphoribosyltransferase (hprt)
gene
Cadmium
carbonate
CdCO3 Insoluble Rusch et al, 1986 Rats
exposed for 2 hours to
CdCO3
at the higher levels of 132 mg/m3
developed rales, rapid breathing,
and
2-3-fold increases in lung weight
Cadmium
chloride
CdCl2 high Takenaka et al,
(1983)
exposed male Wistar
rats to cadmium
chloride aerosol
(MMAD=0.55 μm)
increases in the incidence of lung
tumors , including
adenocarcinomas, squamous cell
carcinomas, and mucoepidermoid
carcinomas
Cadmium nitrate Cd (NO3)2 high Dote et al, 2007 intravenous
administration of CdN
in rats
hyperkalemia associated with
renal injury and hepatic damage
Cadmium
stearate
Cd(C36H72O4) Insoluble Minoru et al, 1974 cerebellar cells from
newborn rat in tissue
culture
inhibited the outgrowth of cells
and produced degenerative
changes at a concentration of 0.58
× 10−66 M
Cadmium sulfate CdSO4 Soluble Bassendowska-
Karska et al, 1987
sister chromatid
exchanges (SCEs) in
lymphocytes of human
peripheral blood
No significant increase was found
in the mean frequency of SCEs in
lymphocytes
Cadmium oxide CdO negligible Sanders and
Mahaffey, 1984
intratracheal instillation
of 25, 50, or 75 μg
cadmium oxide into
male F344 rats
induce d mammary gland tumors,
but not lung tumors
Cadmium sulfide CdS Insoluble Glaser et al, 1990 Inhalation exposure to
Cadmium sulfide
aerosol (90 μg Cd/m3)
observed lung tumors After 4
weeks
International Journal of Scientific Research in Environmental Sciences (IJSRES), 1(8), pp. 202-216, 2013
216
Zienab Saedi is MSc holder in Biotechnology, the Department of Biotechnology, Faculty of Advanced
Sciences and Technologies, University of Isfahan, Isfahan, Iran.
Shahin Gavanji is MSc holder in Biotechnology, the Department of Biotechnology, Faculty of
Advanced Sciences and Technologies, University of Isfahan, Isfahan, Iran. He has over 10 international
medals in invention. Shahin Gavanji's research has focused on Pharmacy and Pharmacology, Nano
Biotechnology, Bioinformatics, Biotechnology - Medical Biotechnology. He is editor in chief of
International Journal of Scientific Research in Inventions and New Ideas.
Sahar Davodi is MSc holder in Biotechnology, the Department of Biotechnology, Faculty of Advanced
Sciences and Technologies, University of Isfahan, Isfahan, Iran.
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